1. Field of the Invention
The present invention relates to a method of treating retrovirus infections, such as HIV and also herpesvirus infections such as human cytomegalovirus (HCMV) infections, and diseases caused by such infections, such as AIDS, ARC and related expressions of human immunodeficiency virus (HIV), such as lymphadenopathy, by administering triciribine, triciribine 5xe2x80x2-monophosphate, the DMF adduct of triciribine, or a pharmaceutically acceptable salt thereof to a patient suffering from HIV infection.
2. Discussion of the Background
Acquired immunodeficiency syndrome (AIDS) and AIDS related complex (ARC) result from infection with human immunodeficiency virus (HIV). The need for an effective treatment of AIDS, ARC and lymphadenopathy is great, due to the continuing increase of HIV infections and consequent opportunistic infections such as HCMV in the population. Current epidemiologic data show that infection with HIV leads to AIDS in over 90% of affected individuals within a ten-year period. Tragically, the number of individuals already infected means that the number of AIDS cases will continue to increase for the foreseeable future.
AZT (zidovudine) has been recommended for the treatment of AIDS and ARC. However, results are less than satisfactory. In particular, AZT therapy is known to cause severe side effects, such as anemia. In addition, there are strains of HIV-1 which are resistant to treatment with AZT.
Thus, there remains a need for an effective treatment of HIV infection and AIDS, ARC, and lymphadenopathy.
Human cytomegalovirus (HCMV) is responsible for many life-threatening infections in immunosuppressed patients such as those receiving organ or tissue transplants, cancer patients, burn patients and those afflicted with AIDS. In addition, intrauterine HCMV infections are second only to Down""s syndrome as a known cause of mental retardation. Ganciclovir (DHPG) is the only drug available for treatment of some of those infections including CMV gastrointestinal infections and CMV retinitis. Unfortunately, prolonged therapy with ganciclovir causes serious side effects, such as neutropenia, which limits its use. Recently, ganciclovir-resistant resistant strains of HCMV have been isolated from AIDS patients undergoing ganciclovir treatment.
Thus, there also remains a need for an effective treatment of HCMV infection.
Accordingly, one object of the present invention is to provide a novel method for the treatment of retrovirus infections.
It is another object of the present invention to provide a method of treating HIV infection.
It is another object of the present invention to provide a method of treating HCMV infection.
It is another object of the present invention to provide a method of treating AIDS.
It is another object of the present invention to provide a novel method for treating ARC.
It is another object of the present invention to provide a novel method for treating lymphadenopathy.
These and other objects, which will become apparent during the following detailed description have been achieved by the inventors"" discovery that AIDS, ARC, and lymphadenopathy may be treated by administering an effective amount of triciribine, triciribine 5xe2x80x2-phosphate, the DMF adduct of triciribine, or pharmaceutically acceptable salts thereof, to a patient in need thereof.
Triciribine (TCN), triciribine 5xe2x80x2-phosphate (TCN-P), and the DMF adduct of triciribine (TCN-DMF) are known compounds having the formulae: 
wherein:
TCN may be synthesized as described in Tetrahedron Letters, vol. 49, pp. 4757-4760 (1971), which is incorporated herein by reference. TCN-P may be prepared as described in U.S. Pat. No. 4,123,524, which is incorporated herein by reference. TCN-DMF is described in INSERM, vol. 81, pp. 37-82 (1978). Triciribine is currently in phase II clinical trials as an anticancer drug.
Thus, the present invention relates to a method of treating retrovirus infections, such as HIV and HCMV infections, and diseases, such as AIDS, ARC, and lymphadenopathy, said method comprising or consisting of administering an effective amount of TCN, TCN-P, TCN-DMF, or a pharmaceutically acceptable salt thereof to a patient in need thereof.
Although the exact dosage of TCN, TCN-P, TCN-DMF, or a pharmaceutically acceptable-salt thereof to be administered will vary according to the size and condition of the patient, a suitable dosage range is 15 to 350 mg/m2 of body surface, preferably 15 to 96 mg/m2 of body surface, most preferably 25 to 50 mg/m2 of body surface.
The TCN, TCN-P, TCN-DMF, or pharmaceutically acceptable salt thereof may be administered according to the present invention by any suitable route, such as intravenously, parenterally, subcutaneously, intramuscularly, or orally. The TCN, TCN-P, TCN-DMF, or pharmaceutically acceptable salt thereof may be administered in any conventional form such as a pharmaceutical composition. Suitable pharmaceutical compositions are those containing, in addition to TCN, TCN-P, TCN-DMF, or pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, such as water, starch, sugar, etc. The composition may also contain flavoring agents and may take the form of a solution, tablet, pill, capsule, etc. The ratio of the weight of TCN, LCN-P, TCN-DMF, or pharmaceutically acceptable salt thereof to the weight of the pharmaceutical composition may, of course, vary but is suitably within 1:1 to 1:5000.
It is to be understood that the present method includes embodiments in which TCN, TCN-P, TCN-DMF, or pharmaceutically acceptable salt thereof is administered to a patient who is also receiving AZT. The present compound(s) and AZT may be administered to the patient in a single composition comprising both the present compounds and AZT. Alternatively, the present compounds) and AZT may be administered separately. Further, the present method includes embodiments in which AZT is administered, without TCN, TCN-P, TCN-DMF, or a pharmaceutically acceptable salt thereof, for a suitable time period of hours, days, or weeks, and the AZT therapy is either preceded or followed by administration of TCN, TCN-P, TCN-DMF, or a pharmaceutically acceptable salt, either with or without AZT.
For purposes of the present invention, the term pharmaceutically acceptable salt thereof refers to any salt of TCN, TCN-P, or TCN-DMF which is pharmaceutically acceptable and does not greatly reduce or inhibit the activity of TCN, TCN-P, or TCN-DMF. Suitable examples for TCN and TCN-DMF include acid addition salts, with an organic or inorganic acid such as acetate, tartrate, trifluoroacetate, lactate, maleate, fumarate, citrate, methane sulfonate, sulfate, phosphate, nitrate, or chloride. Suitable examples of salts for TCN-P include those in which one or more of the acidic phosphate hydrogens has been replaced with an ion, such as sodium, potassium, calcium, iron, ammonium, or mono-, di- or tri-lower-alkyl ammonium, in addition to the acid addition salts described above. It is to be further understood that the terms TCN, TCN-P, TCN-DMF, and pharmaceutically acceptable salts thereof include all the hydrated forms of these compounds as well as the anhydrous forms.
The present method has been found to exhibit the following advantages:
1) Like zidovudine, triciribine is active against both clinical and laboratory stains and isolates of HIV-1 and HIV-2 at concentrations which are not overtly cytotoxic in uninfected cells.
2) Triciribine is active against strains of HIV-1 which have become resistant to zidovudine as a consequence of long term use of zidovudine in patients.
3) Triciribine is active against both HIV and HCXV whereas zidovudine is only active against HIV and ganciclovir is only active against HCKV and other herpesviruses.
4) Triciribine acts by a biochemical mechanism totally different from zidovudine and other antivirals active against HIV and HCMV.
5) The cytotoxicity of triciribine is not synergistic with that of zidovudine in clinically useful dose ranges.
Thus, TCN, TCN-P, and TCN-DMF have been found to inhibit HIV-1 induced RT, p24 core antigen, and infectious virus production in a dose dependent manner using acutely infected H9 and chronically infected H9-IIIB and U1 cells. In a microtiter XTT assay, TCN exhibits an IC50 of 0.26-0.46 xcexcM against HIV-1RF, HIV-IIIB, and HIV-1MN while TCN-P has an IC50 of 0.02-0.03 xcexcM against these isolates. TCN and TCN-P also are active against a panel of HIV-1 and HIV-2 isolates measured by XTT assay. Activity was also demonstrated in fresh human peripheral blood lymphocytes and macrophages infected with clinical isolates of HIV-1, TCN and TCN-P inhibited HIV in chronically infected cells (U1 and CEM) as measured by a reduction in the number of syncytia formed in microtiter assays. HIV resistant to AZT inhibition did not show cross resistance to TCN or TCN-P. In vitro activity was similarly detected against Rauscher MuLV in an UV-XC plaque reduction assay with an observed IC50 of 0.12 xcexcM for TCN and 0.07 xcexcM for TCN-P. RT inhibition assays utilizing TCN, TCN-monophosphate, and TCN-triphosphate have demonstrated that the compounds do not act via inhibition of this enzyme.
Of course, the present invention may be practiced in various embodiments which exclude any step or element not expressly described herein.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.